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Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver‐metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs) by activating the autocrine effect of IL‐1α via the FGFR4‐JAK2‐STAT3 pathway. FGF19‐induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL‐1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19‐induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention. [ABSTRACT FROM AUTHOR]

Abstract Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver‐metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs) by activating the autocrine effect of IL‐1α via the FGFR4‐JAK2‐STAT3 pathway. FGF19‐induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL‐1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19‐induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

Introduction: The mainstay pharmacological approaches to patients with hepatocellular carcinoma (HCC) are tyrosine kinase inhibitors, antiangiogenic agents, and immune checkpoint inhibitors in combination therapy. Aberrant signaling of fibroblast growth factor 19 (FGF19) and its corresponding receptor, fibroblast growth factor receptor 4 (FGFR4), are a driver of HCC cell growth and survival. However, the clinical potential of agents targeting aberrant FGF19/FGFR4 signaling has not been adequately explored., Areas Covered: We evaluate the existing literature on aberrant signaling of FGF19/FGFR4 in HCC and address the recent preclinical and clinical advances of selective FGFR4 inhibitors in the treatment of advanced HCC. Our literature search was performed in September 2021 on clinical trials and ongoing studies published in journals or presented in conferences for cancer research., Expert Opinion: Preclinical studies show selective FGFR4 inhibitors to be highly potent. These inhibitors also show promise in clinical trials and demonstrate manageable on-target side effects. An emphasis should be placed on the development of predictive biomarkers and on enhancing the understanding of primary and acquired resistance mechanisms. This will inspire rationale combination therapy strategies for testing in future clinical trials.

Simple Summary: Considering the high mortality rate and the increasing spread of brain tumors both in adulthood and in childhood, we explore the role and involvement of fibroblast growth factors receptors (FGFRs) in two specific types of brain tumors: astrocytoma and glioblastoma. Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate pivotal cellular processes during embryonal development of the CNS, and as a survival mechanism for adult neurons and astrocytes. Moreover, interactions between the neural cell adhesion molecules NCAM and N-cadherin with FGFR are important for a number of developmental events and have also been implicated in tumor progression. Thus, this review provides an overview on the biological mechanisms of FGFRs related to oncogenesis and a new point of view for future preclinical and clinical studies to develop increasingly targeted therapies. Despite pharmacological treatments and surgical practice options, the mortality rate of astrocytomas and glioblastomas remains high, thus representing a medical emergency for which it is necessary to find new therapeutic strategies. Fibroblast growth factors (FGFs) act through their associated receptors (FGFRs), a family of tyrosine kinase receptors consisting of four members (FGFR1–4), regulators of tissue development and repair. In particular, FGFRs play an important role in cell proliferation, survival, and migration, as well as angiogenesis, thus their gene alteration is certainly related to the development of the most common diseases, including cancer. FGFRs are subjected to multiple somatic aberrations such as chromosomal amplification of FGFR1; mutations and multiple dysregulations of FGFR2; and mutations, translocations, and significant amplifications of FGFR3 and FGFR4 that correlate to oncogenesis process. Therefore, the in-depth study of these receptor systems could help to understand the etiology of both astrocytoma and glioblastoma so as to achieve notable advances in more effective target therapies. Furthermore, the discovery of FGFR inhibitors revealed how these biological compounds improve the neoplastic condition by demonstrating efficacy and safety. On this basis, this review focuses on the role and involvement of FGFRs in brain tumors such as astrocytoma and glioblastoma. [ABSTRACT FROM AUTHOR]